Treatment for altitudinal hypoxia

ABSTRACT

The invention provides a method for treating hypoxia caused by high altitude by administering to a subject a compound that reduces the P 50  of hemoglobin for oxygen.

This application claims priority to U.S. Provisional Application No.61/345,738, filed May 18, 2010, the contents of which are herebyincorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to alleviation of symptoms of hypoxia resultingfrom reduced oxygen levels at high altitudes.

2. Summary of the Related Art

Hemoglobin is the oxygen transporter and regulator in blood. Eachhemoglobin molecule can bind up to four oxygen atoms. The oxygen tension(in millimeters of mercury) at which the oxygen binding sites ofhemoglobin are 50 percent saturated is called P₅₀. P₅₀ is inverselyrelated to the binding affinity of hemoglobin for oxygen. Standard P₅₀is the P₅₀ under standard conditions of 37° C., pH 7.4, carbon dioxidetension of 40 mm Hg at sea level, normally 26.3 mm Hg for a restingadult. However, important physiologic effects are determined by in vivoP₅₀, which changes rapidly in responses to body temperature, carbondioxide tension and pH.

As body temperature increases, the affinity of hemoglobin for oxygendecreases, raising the P₅₀ and facilitating oxygen release. Lacticacidosis due to muscular activity further increases this effect. This isbeneficial during prolonged heavy exercise. High levels of oxygen reduceP₅₀ and increase the affinity of hemoglobin for oxygen. In contrast, lowlevels of oxygen increase P₅₀ and decrease the affinity of hemoglobinfor oxygen.

Taken together, these factors lead to a seriously decreased affinity ofhemoglobin for oxygen under conditions of exercise at oxygen-depletedhigh altitudes. For example, at an altitude of 3,100 m a P₅₀ of 29 mm Hgat rest and 38 mm Hg during heavy exercise have been observed. Thus, theprimary limitation on oxygen transport at high altitude is impairedloading of oxygen onto hemoglobin caused by alveolar hypoxia.

Some animals indigenous to high altitudes, such as yaks, llamas andalpacas have high affinity hemoglobins having P₅₀ about 10 mm Hg lowerthan in related lowland species due to amino acid substitutions in theglobin chain. In fact, humans with the hemoglobin mutationAndrew-Minneapolis, resulting in a P₅₀ of 17 mm Hg, have betterphysiologic function at high altitudes than normal subjects whose P50 is26.3 mm Hg. However, as a result of having evolved at lower altitudes,most humans have an inappropriate increase of P₅₀ at high altitudes,resulting in debilitating symptoms of hypoxia. There is no FDA approveddrug that improves (lowers) the P50 and thus increases Hb affinity foroxygen in normal subjects. However, 5-HMF was evaluated for its effectson P50 in preclinical studies using sickle cell disease (SCD) red cells.These RBCs have a diminished oxygen carrying capacity due to amino acidchanges in Hb structure as a result of a genetic mutation. Abdulmalik,Br. J. Haematol. 128:552-561 (2004), teaches that 5-HMF provides in vivoprotection against the lethal effects of hypoxia in a sickle celldisease mouse model, and that this is the result of a lower P50 (leftshift) in the SCD Hb, thus reducing the formation of sickled red bloodcells in conditions of low oxygen in the inspired air. Thus, accordingto Abdumalik, the beneficial effect of 5-HMF in prolonging survival inthe hypoxic state is due to the inhibition of RBC sickling, a phenomenonthat is unique to SCD and would not be found in normal subjects. Thereis a need for new treatments for alleviating the symptoms of hypoxia innormal humans at high altitudes.

BRIEF SUMMARY OF THE INVENTION

The invention provides a new method for the treatment of altitudinalhypoxia. The method according to the invention comprises administeringto a human subject encountering or about to encounter conditions of lowoxygen a compound that decreases P₅₀ of hemoglobin for oxygen. Themethod according to the invention prevents, reduces or alleviatessymptoms of hypoxia. In preferred embodiments, the compound isadministered at a dosage sufficient to provide in the subject a P₅₀ ofhemoglobin from about 15 mm Hg to about 20 mm Hg under standardconditions of 37° C., pH 7.4, carbon dioxide tension of 40 mm Hg at sealevel. Preferred compounds for such method include5-hydroxymethyl-2-furfural, 5-ethyl-2-furfural, 5-methyl-2-furfural,2-furfural and combinations or prodrugs thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides a new method for the treatment of altitudinalhypoxia. The method according to the invention comprises administeringto a human subject encountering or about to encounter conditions of lowoxygen a compound that decreases P₅₀ of hemoglobin for oxygen, henceincreasing the affinity of Hb for oxygen. The method according to theinvention prevents, reduces or alleviates symptoms of hypoxia. Inpreferred embodiments, the compound is administered at a dosagesufficient to provide in the subject a P₅₀ of hemoglobin from about 15mm Hg to about 20 mm Hg under standard conditions.

For purposes of the invention, the term “a human subject encountering orabout to encounter conditions of low oxygen” means a person who iseither under conditions of low oxygen or about to be under conditions oflow oxygen. The term “low oxygen” is intended to mean a concentration ofoxygen typically found at elevations at or above about 1,500 metersabove sea level and especially at 3,000 or more meters above sea level.The term “standard conditions” means the conditions of an average adultat rest at about 37° C., pH 7.4, carbon dioxide tension of 40 mm Hg atsea level. The term “prevents or alleviates symptoms” means to stop orreduce the development of symptoms or to eliminate or reduce existingsymptoms. “Symptoms” include, without limitation, reduced oxygenation ofblood, red blood cells, and/or tissues, as well as impaired mentalfunction and/or reduced ability to exercise. Such symptoms can bemeasured using standard techniques, such as pulse oximetry, blood gasesanalysis and exercise tolerance testing.

In certain preferred embodiments, the subject is either at, or about tobe transported to, an elevation of from about 1,500 meters to about9,000 meters above sea level. In certain preferred embodiments, thesubject is either at, or about to be transported to, an elevation offrom about 3,000 meters to about 9,000 meters above sea level.

In certain preferred embodiments, the compound is selected from thegroup consisting of 5-hydroxymethyl-2-furfural, 5-ethyl-2-furfural,5-methyl-2-furfural, 2-furfural and combinations or prodrugs thereof. Incertain preferred embodiments, the compound is5-hydroxymethyl-2-furfural or a prodrug thereof. For purposes of theinvention, a “prodrug of a compound” is a derivative of a compound thatis metabolized in vivo to produce the compound. Typically, such prodrugsinclude esters and amides of the compound. Preparation of prodrugs ofpreferred compounds utilizes art recognized techniques, such as thosetaught in U.S. Pat. No. 7,160,910.

In certain preferred embodiments, the compound is administered at adosage sufficient to provide in the subject a P₅₀ of hemoglobin foroxygen of from about 17 mm Hg to about 20 mm Hg under standardconditions. The dosage required to produce such a P₅₀ will depend uponseveral factors, such as the age, weight, health and fitness of thesubject, and can be determined routinely. Preferred compounds for use inthe method according to the invention are non-toxic at theconcentrations to produce the desired P₅₀. For example,5-hydroxymethyl-2-furfural is found in foods that are consumed on adaily basis, such as coffee and caramel products, at a concentrationabove 6 g/kg. In rats, the acute oral LD₅₀ of 5-HMF is 2.5 g/kg formales and 2.5-5.0 g/kg for females (US EPA, 1992).

In some embodiments the human is administered from about 20 mg to about10,000 mg 5-HMF. In some embodiments the human is administered fromabout 20 mg to about 300 mg 5-HMF. In some embodiments the human isadministered from about 20 mg to about 200 mg 5-HMF. In some embodimentsthe human is administered from about 20 mg to about 100 mg 5-HMF. Insome embodiments the human is administered from about 300 mg to about10,000 mg 5-HMF. In some embodiments the human is administered fromabout 300 mg to about 5,000 mg 5-HMF. In some embodiments the human isadministered from about 300 mg to about 3,000 mg 5-HMF. In someembodiments the human is administered from about 300 mg to about 1,500mg 5-HMF. In some embodiments the human is administered from about 1,500mg to about 10,000 mg 5-HMF. In some embodiments the human isadministered from about 1,500 mg to about 5,000 mg 5-HMF. In someembodiments the human is administered from about 1,500 mg to about 3,000mg 5-HMF. In some embodiments the human is administered from about 3,000mg to about 10,000 mg 5-HMF. In some embodiments the human isadministered from about 3,000 mg to about 5,000 mg 5-HMF.

Administration of the compounds can be by any suitable route, including,without limitation, parenteral, oral, sublingual, transdermal, topical,intranasal, inhalation, intratracheal, or intrarectal. In some preferredembodiments, administration is orally, by injection, or by inhalation.

The compounds used in the present invention may be present in anysuitable diluent, carrier or excipient.

The compounds used in the method of the present invention may form saltswhich are also within the scope of this invention. The term “salt(s)”,as employed herein, denotes acidic and/or basic salts formed withinorganic and/or organic acids and bases. Pharmaceutically acceptable(i.e., non-toxic, exhibiting minimal or no undesired toxicologicaleffects, physiologically acceptable) salts are preferred.

As used herein, the term “pharmaceutically acceptable salts” is intendedto mean salts that retain the desired biological activity of thecompounds and exhibit minimal or no undesired toxicological effects.Examples of such salts include, but are not limited to, salts formedwith inorganic acids (for example, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and the like), and saltsformed with organic acids such as acetic acid, oxalic acid, tartaricacid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannicacid, palmoic acid, alginic acid, polyglutamic acid, naphthalenesulfonicacid, naphthalenedisulfonic acid, methanesulfonic acid,p-toluenesulfonic acid and polygalacturonic acid. Other salts includepharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR+Z—, wherein R is hydrogen, alkyl, or benzyl, and Z is acounterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenylacetate).

The following example is intended to further illustrate an embodiment ofthe invention and is not intended to limit its scope.

EXAMPLE Treatment of Hypoxia Induced by Moderate Exercise at ElevatedAltitude

A 40 year old 90 kg male in good health is transported from lowelevation (<100 meters above sea level) to an altitude of 3,000 metersabove sea level and kept at rest there for 3 hours. At that point, thesubject is tested for respiration rate, heart rate and extremity O₂. Thesubject is then put on a stationary exercise bike and allowed to ridethe bike at a cadence of 40 rpm for one hour. The subject is againtested for respiration rate, heart rate and extremity O₂. Then thesubject is transported back to low elevation. The following day, thesubject is again transported to the altitude of 3,000 meters above sealevel and administered a dosage of 5-hydroxymethyl-2-furfural that haspreviously been determined to produce in the subject a P₅₀ of hemoglobinfor oxygen of 18 mm Hg under standard conditions. The subject is kept atrest there for 3 hours, then tested for respiration rate, heart rate andextremity O₂. The subject is then put on a stationary exercise bike andallowed to ride the bike at a cadence of 40 rpm for one hour. Thesubject is again tested for respiration rate, heart rate and extremityO₂. The data from the two days are then compared. It is expected thatthe measured parameters will be closer to normal on day 2 than on day 1.

What is claimed is:
 1. A method for treating a human encountering orabout to encounter conditions of low oxygen comprising administering tothe subject 5-HMF in a dosage sufficient to provide in the subject a P₅₀of hemoglobin from about 15 mm Hg to about 20 mm Hg under standardconditions, wherein the treatment prevents, or reduces, or alleviatessymptoms of hypoxia.
 2. The method according to claim 1, wherein thehuman is at or about to be transported to, an altitude of from about1,500 meters to about 9,000 meters above sea level.
 3. The methodaccording to claim 2, wherein the subject is at, or about to betransported to an altitude of from about 3,000 meters to about 9,000meters above sea level.
 4. The method according to claim 1, wherein thedosage is sufficient to provide in the subject a P₅₀ of hemoglobin fromabout 17 mm Hg to about 20 mm Hg under standard conditions.
 5. Themethod according to claim 1, wherein the human is administered fromabout 300 mg to about 10,000 mg 5-HMF.
 6. The method according to claim1, wherein the human is administered from about 300 mg to about 5,000 mg5-HMF.
 7. The method according to claim 1, wherein the human isadministered from about 300 mg to about 3,000 mg 5-HMF.
 8. The methodaccording to claim 1, wherein the human is administered from about 300mg to about 1,500 mg 5-HMF.
 9. The method according to claim 1, whereinthe human is administered from about 1,500 mg to about 10,000 mg 5-HMF.10. The method according to claim 1, wherein the human is administeredfrom about 1,500 mg to about 5,000 mg 5-HMF.
 11. The method according toclaim 1, wherein the human is administered from about 1,500 mg to about3,000 mg 5-HMF.
 12. The method according to claim 1, wherein the humanis administered from about 3,000 mg to about 10,000 mg 5-HMF.
 13. Themethod according to claim 1, wherein the human is administered fromabout 3,000 mg to about 5,000 mg 5-HMF.
 14. The method according toclaim 1 wherein the compound is administered orally, by injection, or byinhalation.
 15. The method according to claim 1 wherein the compound isadministered daily.